Sympathetic nervous system activity is increased in human essential hypertension and in spontaneously hypertensive rats (SHR). The cause of the increased activity is not known but it persists after blockade of nicotinic ganglion receptors implicating non-cholinergic ganglion transmission as an origin. It is important to know the cause of this activity since it may be involved in the development or maintenance of hypertension. The endogenous sensory peptide substance P (SP) can increase arterial blood pressure by an action on sympathetic ganglia. SP concentration is elevated in ganglia of SHR and depletion of SP lowers blood pressure. SP also lowers blood pressure by a direct action on vascular endothelium. This action is offset in part by the action of SP to stimulate sympathetic ganglia. The long term goal of our research is to elucidate the role of endogenous peptides in cardiovascular regulation. The aim of this proposal is to determine the role of SP in the elevation of blood pressure in hypertension. Observations will be made on power, autospectral and coherence components of renal sympathetic nerve activity (RSNA) and on arterial pressure and heart rate of anesthetized rats. Selective tachykinin agonists will be used in functional studies to identify ganglion tachykinin receptors and selective antagonists used to verify results with the agonists. Quantitative autoradiography will be done to localize the receptors and determine receptor number. These studies will be done in SHR, Wistar-Kyoto rats and Wistar rats to determine the relation of the tachykinin receptor types and receptor number to hypertension. Selective neurokinin receptor antagonists will be administered to determine if endogenous neurokinins contribute to the elevation of blood pressure in SHR. Effects of antagonists on ganglia will be differentiated from potential actions on the vasculature. RSNA, blood pressure, heart rate and responses to selective tachykinins will be evaluated in normotensive rats, in rats with genetic and nongenetic forms of hypertension and in SHR prevented from becoming hypertensive. This is to determine if the enhanced response to SP in SHR is an inherent characteristic of SHR or an adaptive response to the elevated blood pressure. Knowing the receptor type mediating the ganglion action of tachykinins and differences in the role of endogenous tachykinins in the control of sympathetic nerve activity in normotensive and hypertensive rats is of fundamental physiological importance and has potential therapeutic significance in the development of drugs for the therapy of hypertension.